Each year prostate cancer kills over 38,000 Americans, almost twice the number killed by handguns. Bone metastasis is devastating, and no effective therapy exists when the disease becomes hormone refractory. This Prostate SPORE renewal is a multidisciplinary approach to address methods to reduce the incidence, morbidity, and mortality of prostate cancer as follows. Prevention: DNA methylation changes in the human glutathione-S-transferase gene discovered in this grant are the most common genomic alterations reported in prostate cancer, and reversing this is a target of the proposed dietary and chemoprevention studies. Genetics: In families with pedigrees of prostate cancer, genetic linkage studies will identify candidate genes as the Hereditary Prostate Cancer gene. Characterization of cancer genotypes and tumor suppressor gene sequencing will also be conducted. Early Detection and Diagnosis: The velocity of change in serum prostatic specific antigen and serum sex-steroid levels will be correlated with cancer risk in the Baltimore Longitudinal Study of Aging, the world's largest and longest longitudinal aging study. African-Americans have increased prostate cancer incidence and mortality, and this will be studied in the molecular epidemiology of the androgen receptor gene structure. Improved diagnosis and prognosis are studied by new algorithms using new SPORE discovered biomarkers and high resolution quantitative pathology techniques; study of the Kai-1 metastasis suppressor gene; and computational study of chromatin structure in human prostate cancer nuclei. Morbidity Reduction: To accelerate progress in improved prostate cancer patient quality of life, research is focused on the physiology of prostrate cancer bone metastases. Treatment: This SPORE developed the first human gene therapy for advanced prostate cancer which is now NIH RAC approved for clinical trials. New therapies using new vectors for gene therapy, topoisomerase-targeted drugs, immunotherapy, and radiotherapy are being designed. Pilot Projects are targeted on population studies of carcinogens and epidemiological factors; and new drug modalities to enhance cell death. A large core tissue bank has been established to accelerate translation of human prostate research to clinical medicine. New young investigators are being developed and established investigators in other fields are being attracted to study prostate cancer. This is a highly interactive clinical and basic research team dedicated to translate new discoveries to the control of prostrate cancer.